HD is a genetically caused brain disorder that causes uncontrollable bodily movements and robs people's ability to walk, talk, eat, and think. The final result is a slow, ugly death. Children of parents with HD have a 50-50 chance of inheriting the disease. There is no cure or treatment.

HD Blogs and Individuals

Tuesday, June 27, 2017

Ionis Pharmaceuticals has made two positive announcements about the historic
Phase 1 clinical trial of its gene-silencing drug for Huntington’s disease:
trial enrollment is complete, and the company will extend the study for all patients
who complete Phase 1.

These are key steps
on a multi-year path to possible Phase 2 and 3 trials that, if successful, would
bring the trial drug, IONIS-HTTRx, to market. Typically, all three
phases of a clinical trial project take at least five years, although nobody
can predict the actual course of a trial.

IONIS-HTTRx
aims to alleviate HD symptoms by reducing production of the huntingtin protein
in brain cells (click here to read more). Ionis launched the Phase 1 trial in
September 2015. Three dozen
patents are taking part in the trial, expected to be completed by the end of
2017, at sites in Canada, Germany, and England. This first phase aims not to
assess success in combating HD but rather simply whether the drug is safe and
tolerable.

It marks the
first time HD patients are receiving a substance aimed to attack the genetic
causes of the disease. It’s also the first time they’re getting a drug via
spinal injection.

“The safety and
tolerability profile of IONIS-HTTRx in the completed cohorts of the
Phase 1/2a study supports its continued development,” a June 22 Ionis news release stated.
“Patients who complete the Phase 1/2a study will be eligible to participate in
an open-label extension (OLE) study that Ionis plans to initiate in the next
several months.”

“Open label”
means all participants take the drug, in contrast with a “double-blinded” clinical
trial like the current Phase 1, where half the patients receive a placebo and
neither patients nor doctors know who is receiving the actual drug.

This month’s
news provided the strongest indication so far that Ionis and its partner Roche, a much larger multinational pharmaceutical firm with vast clinical
trial experience, will take IONIS-HTTRx into a larger, critical
Phase 2 study, as early as 2018, to measure efficacy.

“Upon completion
and full analysis of this study, the next step for this program will be to
conduct a study to investigate whether decreasing mutant huntingtin protein
with IONIS-HTTRx can slow the progression of this terrible
disease," Frank Bennett, Ph.D., the Ionis senior vice president of research,
said in the release.

Ionis
has repeatedly indicated that a Phase 2 study would include U.S. trial sites.

Frank Bennett, Ph.D. (photo by Kristina Bowyer, Ionis)

‘Cautiously optimistic
news’

The double-blinded
protocol of the Phase 1 HTTRx trial insures that bias and other
external factors don’t affect the trial results.

As noted, in an
OLE each participant receives the actual drug, and usually at the highest dose
tried in Phase 1. An OLE allows researchers to gather more data, examine the
drug’s effects over a longer period of time, and better prepare for an eventual
Phase 2. Patients also potentially benefit by receiving the drug longer.

The HD research
website HDBuzz, which is produced by clinicians and scientists, described the
Ionis announcements as “cautiously optimistic news.”

“News that the
trial is fully recruited and the final patients are going through the
procedures is a strong suggestion that even at the highest doses, the drug’s
safety looks good,” the HDBuzz report observed. “Despite exhaustive safety
testing before going into patients, any drug can produce unwanted effects, so
that’s really the best news we could be hoping to hear at this stage.”

Regarding the
open-label extension, it added, “We don’t want to read too much into a brief
announcement, but running an OLE isn’t cheap for a trial sponsor, so this
announcement certainly gives us optimism about the whole HTTRx
program.”

Signs of HD in the blood

A separate research
study, with results published June 7, could help Ionis and Roche researchers
evaluate the results of the Phase 1 trial and plan the potential Phase 2 trial.

In what was
described as a “major advance in the field of Huntington's disease and
neurodegeneration in general,” a team of researchers has identified a
potential blood biomarker for HD.

Biomarkers indicate
a disease mechanism or drug impact. They are common for many diseases, but the
complexity and inaccessibility of the brain have made it extremely difficult
for researchers to find them for neurological diseases.

HD scientists
have most recently focused on obtaining biomarkers from the cerebral spinal
fluid (CSF). However, obtaining CSF, which requires puncturing the spine, is
far riskier than drawing blood, the technique used in the new biomarker research.

Led by Ed Wild,
M.D., Ph.D., one of the administrators of the IONIS-HTTRx trial in
England, the new biomarker study demonstrated that a brain protein known as
neurofilament light chain (Nfl) appears in the blood of HD patients and
presymptomatic gene carriers. (Click here and
here to read more.)

Dr. Bennett of
Ionis previously described Nfl as a protein involved in the cytoskeleton, or
internal “scaffold,” of neurons. HDBuzz likened it to “the ribs of an
umbrella.”

Dr. Wild’s team
discovered that, the more advanced the stage of HD, the greater the amount of
Nfl in the blood.

“This suggests
that a blood test might be able to provide consistent information about the
brain, in place of an invasive spinal tap,” HDBuzz commented.
“We hope [Nfl] will be added to the arsenal of resources that are helping us to
monitor HD and to develop new therapies.”

Indeed, the
IONIS-HTTRx researchers previously noted that Nfl is one potential
biomarker in the Phase 1 trial.

Further research is underway to confirm the Wild team's results and to determine to what extent Nfl can be used as a biomarker.

Pope Francis, Ionis, and
the hope for a cure

The Ionis
announcements about the clinical trial came as the 32nd annual convention of
the Huntington’s Disease Society of America got underway in Schaumberg, IL. In addition to the news release, Ionis
issued a letter to the HD community.

“We can assure
you our number one goal remains our commitment to advancing IONIS-HTTRx
development, a drug that has the potential to transform the treatment of HD,”
the letter stated.

The positive
news also comes in the wake of HDdennomore, the historic audience of the
Huntington’s disease community with Pope Francis in Rome on May 18.

Dr. Bennett made
a substantial donation to HDdennomore. He and several Ionis officials attended
the audience. Dr. Bennett and his wife Paula sat in the front row along with leading
HD scientists and dignitaries. They were greeted by Francis.

In his address,
the pope recognized the geneticists and scientists “present here, who, for some
time, sparing no energy, have dedicated themselves to studying and researching
a treatment for Huntington’s disease. Clearly, there is a great deal of
expectation surrounding your work: resting on your efforts are the hopes of
finding the way to a definitive cure for the disease, but also of improving the
living conditions of these brothers and sisters, and of accompaniment,
especially in the delicate phases of diagnosis, at the onset of the first
symptoms.”

If it succeeds,
IONIS-HTTRx could fulfill those hopes and show the way to curing
other neurological diseases.

Frank Bennett (left), Paula Bennett, and Gene Veritas (aka Kenneth P. Serbin) in St.
Peter’s Square just before the audience with Pope Francis, May 18, 2017 (photo by Bianca Serbin)